Cardio Pharm Flashcards
*Atorvastatin (10-80 mg)
*Rosuvastatin (5-40 mg)
Lovastatin (20-60 mg) Pravastatin (10-80 mg)
Simvastatin (20-40 mg)
Fluvastatin (20-80 mg)
First two are highest efficacy.
HMG CoA reductase inhibitors (statins)
-rate limiting step in de novo cholesterol synthesis.
SREBP senses low cholesterol is activated,
- tries to increase cholesterol biosynthesis, increase receptor mediated LDL, increase removal of LDL from blood, if high enough decrease VLDL production.
LDL-C decrease 18-55%
HDL-C decrease 5-15%
TG decrease 7-30%
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Pharmacokinetics:
Absorption
– Varies from 40% to 75% except for fluvastatin (almost complete)
– Enhanced by food
• All have high first-pass extraction by liver (site of action)
• Most of absorbed dose excreted in bile
• 5% to 30% excreted in urine (statin-dependent)
• Half-lives
– 1-3 hours except for atorvastatin (14 hours), rosuvastatin (19 hours)
– Hepatic cholesterol biosynthesis maximal midnight -2 AM, take in
evening (except ones with long half-lives)
-metabolized by CYP3A4, taken up for organic anion transporter (OAT) on liver
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Side effects: myopathy, increased liver enzymes, slight risk of new onset diabetes
-Myopathy (with or without elevations in creatine kinase)
▪ Intense myalgia, first in arms and thighs, then entire body; fatigue
▪ Reversible when drug stopped
▪ Rhabdomyolysis > myoglobinuria > renal failure has been reported in
patients with CK levels 10x over normal
▪ Incidence < 0.1% in absence of other drugs that increase risk
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Contraindications:
Absolute: Active or chronic liver disease
Contraindicated in women who are pregnant, lactating or likely to become pregnant (category X, teratogenic)
Relative: Concomitant use of certain drugs
Evolocumab (11-17 days)
Alirocumab (12 days)
PCSK9 inhibitors
(function of PCSK9, • Produced in the ER, undergoes autocatalytic processing and is secreted • Diverts LDLR from recycling pathway towards lysosome for degradation)
-soaks up the PCSK9 and decrease clearance
LDL-C decreases 60%
Hypersensitivity reactions, possibly neurocognitive events
No contraindications
Ezetimibe
cholesterol absorption inhibitors - targets NPC1L1 cholesterol transporter on enterocytes
- decreases delivery of cholesterol to liver
- increase expression of hepatic LDL receptors
- decrease cholesterol content of atherogenic particles
LDL-C decrease around 18%
HDL-C minimal change
TG unknown
Low incidence of reversible impaired hepatic function.
Moderate to severe hepatic impairment.
Cholestyramine
Bile acid sequesterant (resin)
Positive, hydrophobic molecule that binds bile acids facilitating their excretion, the liver needs to make more bile acids so it synthesizes more cholesterol (partially offsets) but also increase LDL receptor mediated endocytosis of LDL and VLDL
Have to take with meals or no effects, should not take with other drugs
LDL-C decrease 15-30%
HDL-C decrease 3-5%
TG No change or even increase
Side effects: GI distress, constipation Decreased absorption other drugs
Contraindications:
Absolute: dysbeta- lipoproteinemia,
TG >400 mg/dL (can increase TAGs)
Relative: TG >200 mg/dL
Colestipol
Bile acid sequesterant (resin)
Positive, hydrophobic molecule that binds bile acids facilitating their excretion, the liver needs to make more bile acids so it synthesizes more cholesterol (partially offsets) but also increase LDL receptor mediated endocytosis of LDL and VLDL
Have to take with meals or no effects, should not take with other drugs
LDL-C decrease 15-30%
HDL-C decrease 3-5%
TG No change or even increase
Side effects: GI distress, constipation
Decreased absorption other drugs
Absolute: dysbeta- lipoproteinemia, TG >400 mg/dL Relative: TG >200 mg/dL
Colesevelam
Bile acid sequesterant (resin)
Positive, hydrophobic molecule that binds bile acids facilitating their excretion, the liver needs to make more bile acids so it synthesizes more cholesterol (partially offsets) but also increase LDL receptor mediated endocytosis of LDL and VLDL
Have to take with meals or no effects, should not take with other drugs
LDL-C decrease 15-30%
HDL-C decrease 3-5%
TG No change or even increase
Side effects: GI distress, constipation
Decreased absorption other drugs
Contraindication
Absolute: dysbeta- lipoproteinemia, TG >400 mg/dL Relative: TG >200 mg/dL
Epinephrine
FA: Anaphylaxis, asthma, open-angle glaucoma; α effects predominate at high doses.
Signiicantly stronger effect at β2-receptor than
norepinephrine.
• Adrenergic receptor activation is dose-dependent
• β1 = β2; α1 = α2 ……. BUTEPI has higher affinity for beta receptors
• Cardiac effects:
– Positive inotrope and chronotrope
(have to be careful in those with diseased heart as this will increase oxygen demand)
Vascular effects:
B2 (skeletal muscle)> a1
-slight reduction in systemic vascular resistance
-diastolic will fall a little bit and so wide pulse pressure results
-higher doses will lead to alpha activity vasoconstriction) overcoming beta2
(Summary of functions)
1.Skeletal muscle - vasodilation, potassium uptake (B2)
2. Metabolism - hyperglycemia (glycogenolysis, gluconeogenesis) , lipolysis (B2),
3. Bronchodilation -inhibits histamine release from mast cells (B2)
4. increased heart rate and contractility (B1)
5. increased renin (B1)
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(Uses)
1. ***drug of choice for anaphylaxis (acute severe allergic reaction)
2. Cardiac arrest
3. Asthma
4. Local anesthetic - (given with alot of epinephrine, the enhanced local vasoconstriction increases the life of the drug)
5. Open angle glaucoma
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(Toxicities)
1. palpitations
2. hypertension
3. Tremor
4. anxiety
-contraindicated in patients on non-selective beta blockers and those with hyperthyroidism (you can get a hypertensive crisis)
Norepinephrine
FA: a1 > a2 > B1: hypotension and septic shock
Dose-dependent responses
alpha 1= alpha 2, beta1 (minimal)
Cardiovascular effects: negligible -effects to the heart.
-Both arterial and venous tone are increased
-increased systolic and diastolic blood pressure, reflex drop in heart rate (baroreceptors) - increased peripheral resistance
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(USES)
1. **hypotension in sepsis
2. **cardiogenic shock
Dopamine (cardio)
D1 = D2 > B > alpha ] Lower doses (due to beta effects): Unstable bradycardia, HF, shock; inotropic and chronotropic Higher doses vasoconstriction at high doses due to α effects.
effects are dose dependent
Low (DA1/DA2)
- increases contractility, HR, Blood pressure minimally
- **renal perfusion increases
Intermediate dose (B1)
- *increases contractility
- increases heart rate, blood pressure and renal perfusion.
High dose (B1 + alpha)
-*increase contractility, heart rate, blood pressure, and risk of arrhythmias
-no real effect on renal perfusion
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USES: hypotension and low cardiac output
TOXICITY: ARRHYTHMIA (both ventricular and supraventricular); wide QRS; angina
What are first line treatments for CHF
1- beta blockers are (generally) contraindicated for a patient with acute- decompensated CHF- this is CHF low EF where the patient is acutely symptomatic, w/low BP etc as the negative inotropic effect can cause further deterioration.
The drugs we discussed that are used in stable CHF are metoprolol and carvedilol
Phenylephrine
Alpha-1 adrenergic agonist
Causes: increased arterial/vascular tone, decreased venous capacitance, causes reflexive decrease in HR.
Hypotension (vasoconstrictor) if can’t use NE, ocular procedures (mydriatic), rhinitis (decongestant), or red eye
Midodrone
Alpha-1 agonist **with black box warning FA: Autonomic insufficiency and postural hypotension. May exacerbate supine hypertension.
Metabolized in liver/tissues to active metabolite. Activates alpha1 receptors > vasoconstriction increasing systolic and diastolic blood pressures while standing, sitting and supine.
Indicated to treat *postural hypotension when nonpharmacologic treatment fails.
Adverse event: SUPINE hypertension
Clonidine
Guanfacine
Alpha Methyldopa
both are alpha2 adrenergic agonists which has central action decreasing SNS outflow.
Decreasing HR, decreasing arterial/venous tone.
Uses: hypertension, anxiolytic, ADHD
(Toxicity): dry mouth, sedation, depression, rebound hypertension
Clonidine: useful for treatment resistant hypertension
Alpha Methyldopa - pregnancy associated hypertension.
Isoproterenol (IV only)
non selective beta agonist, B1 = B2.
B1: increase HR, contractility, conduction velocity
B2: decreased PVR (afterload)
USES: **1. Stokes-Adams attack: Sudden collapse into unconsciousness due to a disorder of heart rhythm in which there is a slow or absent pulse resulting in syncope (fainting) with or without convulsions. In this condition, the normal heartbeat passing from the upper chambers of the heart to the lower chambers is interrupted. TLDR: syncope due to slow or absent pulse
- cardiac arrest
- heart block
- evaluation of tachyarythmia
TOXICITY
- tachycardia
- Hypertension
- Dysrhythmia
Dobutamine (IV only)
Beta 1 selective agonist + some alpha 1 activity (just to be fucking annoying)
- *increased contractility > chronotropic effect
- alpha1 action maintains peripheral resistance
USES:
#1 drug for cardiogenic shock with maintained BP
-add to NE in septic shock with low CO
-stress test
TOXiCITY:
- Tachyarrhythmia
- Premature ventricular contractions
- Hypertension
Albuterol (short)
Salmeterol (long)
Acts on beta 2 receptors in lung
Uses: Asthma, bronchospasm
Toxicity: tremor, nervousness
Amphetamine
Cocaine
Indirect and mixed sympathomimetics
-primarily their cardiac effects are due to increased NE in the synapse
Cocaine: inhibits reuptake of NE
Amphetamine is possibly reversing reuptake transporter and pushing NE out. (in addition to dopamine and serotonin)
Phenoxybenzamine
ONLY IRREVERSIBLE, non-selective alpha receptor antagonist - alpha1 > alpha2. Lasts 14-48 hrs. Blocks NE reuptake at presynaptic terminals.
CV effects:
- lower PVR (block alpha 1)
- decrease BP
- orthostatic hypotension and reflex tachycardia.
- miosis
- nasal stuffiness
- decreased resistance to urinary flow
USES: treatment of Pheochromocytoma (adrenal medullary tumor secreting way too much catecholamine)
ADverse effects: postural hypotension, reflex tachycardia, nasal stuffiness, fatigue, nausea. Contraindicated with nonselective beta blockers
Phentolamine (IV or IM only)
REVERSIBLE nonselective alpha antagonist alpha 1 = alpha 2
Blocks peripheral resistance, alpha 2 antagonism causes cardiac stimulation
- treatment of Pheochromocytoma
- use in NE extravasation (you want NE to leak form the blood vessel or tube)
Adverse effects: severe tachycardia, arrhythmias, MI
A 74 year old is admitted for perforated sigmoid diverculitis and subsequently develops hypotension.
Sepsis is suspected.
The patient fails to respond to intravenous fluid resuscitation so they are started on a norepinephrine infusion.
A few hours later blanching, pallor and induration of the skin are noted around the infusion site. Local injection of which of the following agents is most likely to be of greatest benefit?
A. Calcium gluconate
B. Phentolamine
C. Heparin
D. Isoproterenol
E. Lidocaine
Phentolamine - NE extravasation
Prazosin
Terazoin
Doxazosin
HIGHLY selective alpha1 antagonism (1000x > a2)
- less effects on the heart
- relaxes arterial and venous smooth muscle
- *relaxes smooth muscle in the PROSTATE (relaxes the sphincter) - mostly used in BPH now
USES: *hypertension (not indicated as first line) and BPH
Doxazosin is the longest half life at 22 hours
Toxic events:
- Orthostatic hypotension
- dizziness, headache
- drowsiness
- ejaculation problems
Tamulosin
Uroselective selective alpha 1 antagonist
blocks alpha1 and D1 receptors in prostate so more selective for BPH
Yohimbine
Alpha 2 selective antagonist
- used for erectile dysfunction
- works in the CNS to increase SNS outflow to the periphery
CONtraindicated in CV disease
-this is the opposite of clonidine
Esmolol - Beta1 selective, 2nd gen
Metoprolol - Beta1 selective, 2nd gen
Propranolol -(nonselective, 1st gen)
Labetolol - nonselective, 3rd gen
Carvediol - nonselectie 3rd gen
Nebivolol - beta1 selective 3rd gen
PK)
-Esmolol: shortest half life of only 10 minutes
-Nadolol and Nebivolol have the longest half life 10-30 hrs
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CV EFFECTS
1. negative chronotrope - slows heart rate, slowed AV conduction with increased PR interval
- negative inotrope - decreases contractility, decreases CO, worload and use of O2.
- (Beta1) - lowering of high blood pressure, suppression of renin release but ONLY effective if you have high blood pressure
- Blockade of B2 in periphery can cause increase PVR
- Bronchoconstriction (contraindicated w/severe obstructive disease)
- Metabolic and endocrine effects: blocks lipolysis leading to increased VLDL, decreased HDL, impaired glucose tolerance
- Reduce intraocular pressure
8, *Labetolol, antagonism of beta1=beta2, antagonism of alpha1. Actions on both contribute to fall in hypertension, alpha1 antagonism leads to vasodilation. The beta1 blockage also contributes to fall in BP, blocking reflex sympathetic stimulation
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USE:
1. coronary artery disease so that cardiac oxygen supply and demand is improved.
- hypertension - lowers BP in individuals with hypertension, decrease CO, renin, Systemic vascular resistence over time, **NOT 1st LINE
- MI - propranolol in acute STEMI
- HF
- hyperthyroidism
- Glaucoma
7 Migraine
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(ADVERSE EFFECTS) - Drug rebound - can precipitate acute MI in patients if you discontinue, ventricular tachyarrhythmia
- CHF exacerbation - *acute
- Bradyarrythmia - AV conduction defect can lead to serious bradyarrhthmia
- Bronchoconstriction
- Worsens glycemic control in type 2 (lipid metabolism decreases, weight gain)
Heparin
Antithrombin III activator
- highly sulfated mucopolysaccharide , highly negative
- not absorbed from GI tract, not effective orally.
-allosteric binding exposes a reactive site accessible to Factor Xa and thrombin
-heparin is then released and still cna form more antithrombin-protease complexes.
-Unfractionated heparin has higher specificity as it can make a complex with both Antithrombin and thrombin (as opposed to LMW heparin)
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Reversal of heparin action:
-discontinue usage of the drug
-protamine sulfate is an effective antidote (fish sperm highly positive), only effective against LMWH and itself has anticoag activity.
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Toxicity:
1. major bleeding
2. Osteoporosis (higher with UFH)
3. Heparin resistance - elevated factor VIII or other proteins, antithrombin deficiency, increased clearance
4. Heparin induced thrombocytopenia- heparin acts as a haptin, antibodies are binding and activating platelets, platelet count will drop in plasma and you clot because platelets are releasing particles that activate thrombin.
Enoxaparin
indirect thrombin inhibitor (relative to heparin)... \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ -less inhibition of thrombin -efficiently inhibit factor Xa activity -longer half life (4.5 hrs) less frequent dosing
Uses:
- prevention of DVT in postsurgery
- treat acute venous thromboembolic disease and acute coronary syndromes
- more predictable bioavailability
Fondaparinux
indirect thrombin inhibitor
Synthetic analog of the pentasaccharide binding sequence of heparin *target is only Factor Xa \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ • Pharmacokinetics – long half-life (17-21 h) – 100% bioavailable after a single, daily, subcutaneous dose – Renal clearance, should not be given to patients with renal impairment • Low incidence of HIT *more predictable bioavailability
Desirudin
65 amino acid protein found in medicinal leech (Hirudo medicinalis).
• Most potent known inhibitor of thrombin.
• Action is independent of antithrombin III
• Can reach and inactivate fibrin-bound thrombin in thrombi
• Does not cause thrombocytopenia • Approved- prevention of deep vein thrombosis post elective hip replacement
•t1/2 = 2 hours
• Renal clearance
-binds to exosite 1 of thrombin and catalytic (active) site
Bivalirudin
(Direct thrombin inhibitor)
• Synthetic peptide congener of hirudin
• Short half life (~25 min) • Clearance: renal & metabolic
• FDA approved for use in coronary angioplasty, also in patients
with HIT
-binds to exosite 1 of thrombin and catalytic (active) site
Argatroban
-direct thrombin inhibitor (only binds to active site of thrombin)
• Administered IV • FDA approved for use as an anticoagulant in patients with heparin-induced thrombocytopenia (HIT).
• Pharmacokinetics
• Half-life 40-50 minutes.
• metabolized by the liver and eliminated in the bile
• Monitored by aPTT, also prolongs PT (note when use with warfarin).
• aPTT returns to normal two hours after discontinuing treatment.
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[Adverse effects]
• hemorrhage (2%)
• allergic reactions (10%)
Warfarin (*oral anticoagulant)
99% bound to albumin (drug interactions)
-inhibits biosynthesis of vitamin K dependent zymogens
[Procoag] Prothrombin Factor VII Factor IX Factor X
[Anticoag]
Protein C
Protein S
MOA: blocks vitamin K reductase VKORC1 activity, reduced vitamin K is needed by glutamyl carboxylase to make functional zymogens by carboxylating and making GLA residues.
-Early on with usage, protein C level goes down early and you are in a procoagulant state.
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warfarin has a low therapeutic index
1.-bleeding
2. Birth defects and abortion
-Skeletal and CNS abnormalities (hypoplastic nose, flat face, altered calcification)
-Contraindicated during pregnancy (heparin may be used)
- Skin necrosis
- Microvascular thrombosis
- May occur in patients with heterozygous protein C or S deficiency if a high initial dose is used or heparin overlap is inadequate
Dabigatran
direct thrombin inhibitor
Non-inferiority/superiority to warfarin Less intracranial bleeding than warfarin (at least 50% lower)
**GI bleeding higher for dabigatran, rivaroxaban and edoxaban
Other sites, similar overall bleeding
Similar uses to warfarin but contraindicated in patients with mechanical heart valves
**Claimed that routine coagulation monitoring not necessary due to predictable response (benefit)
Antidote for Dabigatran: Idarucizumab, humanized mAb
Rivaroxaban
Non-inferiority/superiority to warfarin Less intracranial bleeding than warfarin (at least 50% lower)
**GI bleeding higher for dabigatran, rivaroxaban and edoxaban
Other sites, similar overall bleeding
Similar uses to warfarin but contraindicated in patients with mechanical heart valves
**Claimed that routine coagulation monitoring not necessary due to predictable response (benefit)
Apixaban
direct factor Xa inhibitor
Non-inferiority/superiority to warfarin Less intracranial bleeding than warfarin (at least 50% lower)
**GI bleeding higher for dabigatran, rivaroxaban and edoxaban
Other sites, similar overall bleeding
Similar uses to warfarin but contraindicated in patients with mechanical heart valves
**Claimed that routine coagulation monitoring not necessary due to predictable response (benefit)
Edoxaban
Non-inferiority/superiority to warfarin Less intracranial bleeding than warfarin (at least 50% lower)
**GI bleeding higher for dabigatran, rivaroxaban and edoxaban
Other sites, similar overall bleeding
Similar uses to warfarin but contraindicated in patients with mechanical heart valves
**Claimed that routine coagulation monitoring not necessary due to predictable response (benefit)
Alteplase
recombinant tPA
Physiologically t-PA activates plasminogen that is bound to fibrin of thrombus,
• plasmin activation at the site of clot is several hundred times higher than unbound plasminogen.
• Clinical concentrations are much higher than physiological concentrations
• Non-specific plasmin activation
• Half-life ~ 5 min in plasma. Typically IV bolus then infusion
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• Approved uses
- Acute MI
- Acute ischemic stroke
- Pulmonary embolism
- Central venous catheter occlusion
[Absolute Contraindications] • Prior intracranial hemorrhage • Known structural cerebral vascular lesion • Known malignant intracranial neoplasm • Ischemic stroke within 3 months • Suspected aortic dissection • Active bleeding or bleeding diathesis (excluding menses) • Significant closed-head trauma or facial trauma within 3 months
[Relative Contraindications] • Uncontrolled hypertension
(systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg) • Traumatic or prolonged CPR or major surgery within 3 weeks • Recent (within 2-4 weeks) internal bleeding • Noncompressible vascular punctures • Pregnancy • Active peptic ulcer • Current use of warfarin and INR >1.7
Aspirin (in terms of cardiac) - acetyl salicylic acid
Aspirin inhibits thromboxane A2 (TxA2) synthesis by irreversibly acetylating cyclooxygenase-1 (COX-1). Reduced TxA2 release attenuates platelet activation and recruitment to the site of vascular injury.
Platelets have no nucleus & cannot regenerate COX. Effect lasts the life of the platelet (7-10 days).
•Endothelial cells can regenerate COX to produce PGI2, restoring antithrombotic effect.
•Endothelial cyclooxygenase requires higher doses of aspirin for inhibition. Low dose (70-325 mg/day) can selectively inhibit platelet COX, sparing endothelial COX and thus sustaining antithrombotic effect.
•Primary prophylaxis of myocardial infarction; secondary prevention vascular events following heart disease •Adverse effects: BLEEDING (hemorrhagic stroke, GI bleeding), risk of peptic ulcer disease
Clopidogrel
Irreversibly inhibits the binding of ADP to its receptor on platelets, inhibits platelet aggregation
((blocks P2Y12, a key ADP receptor on the platelet surface; cangrelor and ticagrelor are reversible inhibitors of P2Y12.)
[Indications and; adverse effects]
• Dual antiplatelet therapy (e.g., coronary artery stenting)
– ADP inhibitor + aspirin
• Triple therapy (e.g., coronary artery stenting plus atrial fibrillation)
– Oral anticoagulant + ADP inhibitor + aspirin
• BLEEDING
Prasugrel
Irreversibly inhibits the binding of ADP to its receptor on platelets, inhibits platelet aggregation
((blocks P2Y12, a key ADP receptor on the platelet surface; cangrelor and ticagrelor are reversible inhibitors of P2Y12.)
Indications and; adverse effects • Dual antiplatelet therapy (e.g., coronary artery stenting)
– ADP inhibitor + aspirin • Triple therapy (e.g., coronary artery stenting plus atrial fibrillation)
– Oral anticoagulant + ADP inhibitor + aspirin • BLEEDING
thrombotic thrombocytopenia purpurae
Abciximab
GPIIb/IIIa is a platelet membrane receptor which binds to the fibronogen and vitronectin and also to fibronectin and von Willebrand Factor, facilitates formation of platelet plug.
monoclonal antibody directed against GPIIb/IIIa complex
• approved for use in coronary angioplasty and in acute coronary syndrome.
Ticagrelor/ticlopidine
Reversibly inhibits the binding of ADP to its receptor on platelets, inhibits platelet aggregation
(blocks P2Y12, a key ADP receptor on the platelet surface; ticagrelor is the only reversible inhibitors of P2Y12.)\
***-ticlopidine - causes neutropenia
-metabolized by P450 enzymes so poor metabolizers are more at risk
Indications AND; adverse effects • Dual antiplatelet therapy (e.g., coronary artery stenting)
– ADP inhibitor + aspirin • Triple therapy (e.g., coronary artery stenting plus atrial fibrillation)
– Oral anticoagulant + ADP inhibitor + aspirin • BLEEDING
-thrombotic thrombocytopenia purpurae
